Alcohol abuse remains one of the major health problems with approximately 14 million Americans (<5% of total population) suffering from alcohol abuse. However, the prevalence of chronic alcohol consumption among HIV-positive individuals has been reported to be between 29 and 60% in US. In view of emerging results from several laboratories, it is becoming clear that alcohol abuse contributes to HIV replication, disease progression and development of HIV-associated dementia. Furthermore both alcohol and HIV are independently known to be neurotoxic, but it is not known with certainty whether they will have synergistic effect in alcohol addicted HIV-1 positive individuals and cause increased production of proinflammatory. This application is designed to address this gap in the existing knowledge. We will study the combined effect of the alcohol and 2 virotoxins (HIV-1 gp120 and Tat,) on cytokine as well chemokine production, markers of oxidative stress, apoptosis, PPAR-? in astrocytes/neurons, and whether these detrimental effects can be abrogated by use of the antagonists of alcohol metabolism, the virotoxin-specific siRNAs and PPAR-? agonists. These in vitro studies will be extended to in vivo situation where effect of chronic alcohol consumption will be studied in HIV-1 Tat and gp120 transgenic mice. These mice will be used for assessment of cytokine and chemokine expression, neuronal apoptosis in brain as well as leakage in the blood brain barrier and whether use of alcohol antagonist and PPAR-? agonists will abrogate the alcohol-mediated neurotoxicity. PUBLIC HEALTH RELEVANCE: This application proposes to dissect mechanism of increased neuroinflammation in alcohol-dependent HIV-1-infected individuals. We will study the role of proinflammatory cytokines and chemokine and whether their over-expression in the CNS leads to increased neurotoxicity. We will also determine role of antagonist of alcohol metabolism, siRNA and PPAR-gamma agonists in the management of neuroinflammation. These in vitro results will be extended to an in vivo model system using transgenic mice.